A mathematical model was used to derive operational equations to examine incorporation and turnover of long chain fatty acids within brain phospholipids under in vivo conditions. The model was applied when using a new rapid method to analyze brain acyl-CoA, the precursor pool for fatty acid incorporation into phospholipids. Chronic treatment of rats with lithium reduced turnover of arachidonic acid by 80% in phosphatidylinositol and phosphatidylcholine, but had no effect on palmitate or docosahexaenoate turnover. As lithium also inhibited brain phospholipase A2, an arachidonic-specific phospholipase A2 was proposed as a target for the action of lithium in treating bipolar disorder. Following transient forebrain ischemia in gerbils, there was a massive release of fatty acids. Reuptake into brain phospholipids was selective for arachidonic acid. Studies in monkeys using positron labeled fatty acids demonstrated measurable brain incorporation using positron emission tomography (PET). Incorporation was independent of cerebral blood flow. A clinical PET protocol was initiated to examine fatty acid incorporation in healthy young and old subjects and in patients with Alzheimer disease.